Neuregulin-1 controls an endogenous repair mechanism after spinal cord injury

Abstract

Following traumatic spinal cord injury, acute demyelination of spinal axons is followed by a period of spontaneous remyelination. However, this endogenous repair response is suboptimal and may account for the persistently compromised function of surviving axons. Spontaneous remyelination is largely mediated by Schwann cells, where demyelinated central axons, particularly in the dorsal columns, become associated with peripheral myelin. The molecular control, functional role and origin of these central remyelinating Schwann cells is currently unknown. The growth factor neuregulin-1 (Nrg1, encoded by NRG1) is a key signalling factor controlling myelination in the peripheral nervous system, via signalling through ErbB tyrosine kinase receptors. Here we examined whether Nrg1 is required for Schwann cell-mediated remyelination of central dorsal column axons and whether Nrg1 ablation influences the degree of spontaneous remyelination and functional recovery following spinal cord injury. In contused adult mice with conditional ablation of Nrg1, we found an absence of Schwann cells within the spinal cord and profound demyelination of dorsal column axons. There was no compensatory increase in oligodendrocyte remyelination. Removal of peripheral input to the spinal cord and proliferation studies demonstrated that the majority of remyelinating Schwann cells originated within the injured spinal cord. We also examined the role of specific Nrg1 isoforms, using mutant mice in which only the immunoglobulin-containing isoforms of Nrg1 (types I and II) were conditionally ablated, leaving the type III Nrg1 intact. We found that the immunoglobulin Nrg1 isoforms were dispensable for Schwann cell-mediated remyelination of central axons after spinal cord injury. When functional effects were examined, both global Nrg1 and immunoglobulin-specific Nrg1 mutants demonstrated reduced spontaneous locomotor recovery compared to injured controls, although global Nrg1 mutants were more impaired in tests requiring co-ordination, balance and proprioception. Furthermore, electrophysiological assessments revealed severely impaired axonal conduction in the dorsal columns of global Nrg1 mutants (where Schwann cell-mediated remyelination is prevented), but not immunoglobulin-specific mutants (where Schwann cell-mediated remyelination remains intact), providing robust evidence that the profound demyelinating phenotype observed in the dorsal columns of Nrg1 mutant mice is related to conduction failure. Our data provide novel mechanistic insight into endogenous regenerative processes after spinal cord injury, demonstrating that Nrg1 signalling regulates central axon remyelination and functional repair and drives the trans-differentiation of central precursor cells into peripheral nervous system-like Schwann cells that remyelinate spinal axons after injury. Manipulation of the Nrg1 system could therefore be exploited to enhance spontaneous repair after spinal cord injury and other central nervous system disorders with a demyelinating pathology.media-1vid110...

ErbB receptor signaling directly controls oligodendrocyte progenitor cell transformation and spontaneous remyelination after spinal cord injury

“…In light of our previous findings which showed that selective ablation of Nrg1 prevents spontaneous Schwann cell mediated remyelination after SCI (Bartus et al, ), our data now reveal that ErbB tyrosine kinase receptor activation controls the differentiation of centrally derived progenitor cells from the PDGFRα lineage, presumably OPCs, into PNS‐like Schwann cells that remyelinate CNS axons after traumatic SCI and significantly contribute to spontaneous locomotor recovery. These data reveal a novel role for ErbB tyrosine kinase receptor signaling after CNS injury, providing important mechanistic insight as to the molecular signaling driving spontaneous regenerative remyelination and functional repair after SCI which may also have important implications in other CNS disorders with a demyelinating pathology.…”

“…It remains unknown how and why glial progenitor cells of central origin can transform into remyelinating Schwann cells after demyelinating injuries (Assinck, Duncan, Plemel, et al, ; Zawadzka et al, ). Given our recent evidence that global deletion of Nrg1 prevents Schwann cell remyelination in the dorsal columns after traumatic SCI, and that many remyelinating Schwann cells appear to be newly formed intrinsically within the spinal cord after injury (Bartus et al, ), we hypothesized that Nrg1 is a key molecular signal that underlies the differentiation of OPCs.…”

“…To assess whether centrally derived remyelinating Schwann cells could contribute to functional recovery after SCI, we monitored injured mice for spontaneous locomotor recovery using the inclined beam‐walking test as described previously (Bartus et al, ), the 10‐point BMS, and 12‐point BMS open field hind limb locomotion subscore, to delineate recovery of fine locomotor features that are not apparent in the overall BMS score (Bartus et al, ; Basso et al, ). Assessment of open field locomotion during 8 weeks of post‐injury recovery using the BMS scale revealed no significant differences in locomotor recovery between injured control animals and animals lacking ErbB receptors in PDGFRα‐expressing progenitor cells (Figure a; two‐way repeated measures ANOVA , p > .05, N = 9–10, PDGFRα/+ErbB3/4 versus PDGFRα/‐ErbB3/4).…”

“…One spontaneous repair response triggered after SCI, albeit suboptimally, includes remyelination of surviving spinal axons which partially restores function (Assinck, Duncan, Plemel, et al, ; Bartus et al, ; James et al, ; Papastefanaki & Matsas, ; Plemel et al, ). Both oligodendrocyte‐ and Schwann cell‐mediated remyelination take place following SCI (Bunge, Bunge, & Ris, ; Bunge, Puckett, Becerra, Marcillo, & Quencer, ; Guest, Hiester, & Bunge, ), where it has been suggested that while oligodendrogenesis is an ongoing process in chronic SCI (Hesp, Goldstein, Miranda, Kaspar, & McTigue, ), Schwann cells may migrate into the injured spinal cord from the peripheral nervous system (PNS) following breakdown of the glial limitans (Franklin & Blakemore, ; Guest et al, ).…”

Understanding the NG2 Glial Scar after Spinal Cord Injury

“…However, genetic lineage tracing revealed that, after focal demyelination in the dorsal column white matter, the majority of Schwann cells were derived from NG2 cells (94). This is also supported by a recent study in which a dorsal rhizotomy did not lead to a significant decrease in Schwann cells at the SCI site, indicating that the peripheral nervous system (PNS) is not a major source of Schwann cells present at the injury site (95). While there is accumulating evidence that NG2 cells can differentiate into Schwann cells after SCI, there are several issues that need to be carefully considered.…”